Natalizumab disproportionately increases circulating pre-B and B cells in multiple sclerosis.
BACKGROUND
Natalizumab, a humanized anti-alpha4 integrin monoclonal antibody, reduces relapses and disease progression in patients with multiple sclerosis (MS). Whereas its presumed mode of action is inhibition of T cell/monocyte entry into the brain, little is known about its specific effect on B cells, which are increasingly recognized to participate in MS pathogenesis.


METHODS
We obtained serial blood samples from 17 patients before and during natalizumab therapy for relapsing-remitting MS for up to 16 months, and blood samples from 10 untreated patients with MS and 13 healthy donors. We determined numbers of mature and immature lymphocyte subsets by flow cytometry for CD3, CD4, CD8, CD19, CD138, and CD10 in 111 samples. We analyzed marker transcripts for immature hematopoietic cells by quantitative PCR for CD34, Vprebeta1 (pre-B lymphocyte gene 1), and DNTT (terminal deoxynucleotidyltransferase) in 65 samples.


RESULTS
Natalizumab therapy increased CD19(+) mature B cells more than other lymphocytes/monocytes in blood (2.8-fold versus 1.3-1.8-fold increase in cells/microL; p < 0.01). Even greater was the increase of immature CD19(+)CD10(+) pre-B cells (7.4-fold; p < 0.01). This pattern remained stable during treatment for up to 16 months. Transcripts of lymphocyte precursors (Vprebeta1 and DNTT) were elevated more than transcripts for CD34.


CONCLUSIONS
Circulating B cells and especially pre-B cells are most prominently elevated among the studied immune cell subsets, raising the possibility that the effects and side effects of natalizumab are partly mediated by actions on B cells.
Krumbholz
M
M
Institute of Clinical Neuroimmunology, Ludwig Maximilians University, Munich, Germany.
Meinl
I
I
Kümpfel
T
T
Hohlfeld
R
R
Meinl
E
E
D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002464:Cell Migration Inhibition / Q000276:immunology; D006801:Humans; D018655:Lymphocyte Count; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D000069442:Natalizumab; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D011446:Prospective Studies; D013997:Time Factors
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000069442:Natalizumab